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Inhibition of G1 phase cyclin dependent kinases by transforming growth factor beta 1

K B Reddy1, B A Hocevar, P H Howe

  • 1Department of Cell Biology, Cleveland Clinic Research Institute, Ohio 44195.

Journal of Cellular Biochemistry
|November 1, 1994
PubMed

Insights

Transforming growth factor beta 1 (TGF beta 1) inhibits epithelial cell proliferation by targeting key cell cycle regulators. This growth factor disrupts the activity of cyclin-dependent kinases, leading to cell cycle arrest in late G1 phase.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Transforming growth factor beta 1 (TGF beta 1) is a known inhibitor of epithelial cell proliferation.
  • TGF beta 1 exerts its inhibitory effects late in the G1 phase of the cell cycle.
  • The precise molecular mechanisms underlying TGF beta 1-induced growth arrest require further elucidation.

Purpose of the Study:

  • To investigate the impact of TGF beta 1 on specific late G1 cell cycle regulators.
  • To determine the molecular targets of TGF beta 1 responsible for inhibiting cell proliferation.
  • To elucidate the role of p33cdk2, cyclin A, and cyclin E in TGF beta 1-mediated cell cycle arrest.

Main Methods:

  • Assessed the effect of TGF beta 1 on histone H1 kinase activity associated with p33cdk2, cyclin A, and cyclin E.
  • Analyzed the synthesis of p33cdk2, cyclin A, and cyclin E proteins in response to TGF beta 1.
  • Investigated the cell cycle-dependent effects of TGF beta 1 on cyclin A synthesis.

Main Results:

  • TGF beta 1 inhibits the late G1 and S phase histone H1 kinase activity of p33cdk2.
  • Inhibition of p33cdk2 kinase activity is due to decreased phosphorylation, not altered synthesis.
  • TGF beta 1 inhibits both cyclin A and cyclin E-associated histone H1 kinase activities.
  • TGF beta 1 inhibits cyclin A synthesis in a cell cycle-dependent manner, with no effect if added after 8 hours into G1.
  • TGF beta 1 does not affect cyclin E synthesis.

Conclusions:

  • TGF beta 1 targets and inhibits the kinase activity of p33cdk2, cyclin A, and cyclin E.
  • These G1 cyclin-dependent kinases are key molecular targets for TGF beta 1-mediated growth arrest.
  • The findings provide a molecular basis for TGF beta 1's role as a physiological inhibitor of cell proliferation.

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